Family and twin studies support a significant genetic component in the trait of male homosexuality, one of the most fundamental variations in normal human sexuality. This application describes an effort composed of five investigators at the University of Chicago, one investigator at Northwestern University, and one ethicist consultant at the University of Illinois at Chicago, whom have been selected to provide special strengths for recruiting a large number of affected sib pairs (ASPs) comprised of homosexual brothers, and increasing the understanding of the genetic contributions to this trait. We are fully aware of the difficulties that all studies in this field have faced in studying this area without the benefit samples of adequate size. Considerable thought has gone into designing an ascertainment procedure that eliminates obstacles to achieving a larger sample. We have designed our study so that a total sample of 1,000 ASPs can be achieved within three years. An estimate of the sibling recurrence ratio (Isib) for the trait is approximately bh2 to 4. Power analyses demonstrate that a sample of 1,000 ASPs will have substantial power to detect predisposing loci for a complex trait such as male homosexual orientation: approximately 80% power to detect loci Isib greater than 1.25 for "suggestive" linkage (p=0.00074), and approximately 80% power to detect loci Isib greater than 1.3 for "significant" linkage (p=0.000022). All of the investigators are experienced in modern family study methods and in procedures for establishing the phenotype of male homosexual orientation (Kinsey score of 5-6). All are experienced in collaborative research studies, with one site having collected samples for the largest linkage study of male homosexual orientation to date, and the other site having collected similar samples in the course of family and twin studies of male homosexual orientation. Our large region-wide and national recruitment efforts by experienced researchers will ensure that we can recruit 1,000 pairs of homosexual brothers within 3 years through the above opportunistic ascertainment. Years 4 and 5 of the project are dedicated to completing a 10cM genome scan, fine-mapping, association analyses, and the secondary analyses for the fraternal birth order effect and the quantitative trait of childhood gender nonconformity.